Hexham J M, White K D, Carayannopoulos L N, Mandecki W, Brisette R, Yang Y S, Capra J D
Molecular Immunogenetics Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
J Exp Med. 1999 Feb 15;189(4):747-52. doi: 10.1084/jem.189.4.747.
Polymeric immunoglobulins provide immunological protection at mucosal surfaces to which they are specifically transported by the polymeric immunoglobulin receptor (pIgR). Using a panel of human IgA1/IgG1 constant region "domain swap" mutants, the binding site for the pIgR on dimeric IgA (dIgA) was localized to the Calpha3 domain. Selection of random peptides for pIgR binding and comparison with the IgA sequence suggested amino acids 402-410 (QEPSQGTTT), in a predicted exposed loop of the Calpha3 domain, as a potential binding site. Alanine substitution of two groups of amino acids in this area abrogated the binding of dIgA to pIgR, whereas adjacent substitutions in a beta-strand immediately NH2-terminal to this loop had no effect. All pIgR binding IgA sequences contain a conserved three amino acid insertion, not present in IgG, at this position. These data localize the pIgR binding site on dimeric human IgA to this loop structure in the Calpha3 domain, which directs mucosal secretion of polymeric antibodies. We propose that it may be possible to use a pIgR binding motif to deliver antigen-specific dIgA and small-molecule drugs to mucosal epithelia for therapy.
聚合免疫球蛋白在黏膜表面提供免疫保护，它们通过聚合免疫球蛋白受体（pIgR）被特异性转运至这些黏膜表面。利用一组人IgA1/IgG1恒定区“结构域交换”突变体，二聚体IgA（dIgA）上pIgR的结合位点被定位到Cα3结构域。选择与pIgR结合的随机肽并与IgA序列进行比较，结果表明，在Cα3结构域的一个预测暴露环中，氨基酸402 - 410（QEPSQGTTT）是一个潜在的结合位点。该区域两组氨基酸的丙氨酸取代消除了dIgA与pIgR的结合，而在该环紧邻的NH2末端β链中的相邻取代则没有影响。所有与pIgR结合的IgA序列在该位置都含有一个IgG中不存在的保守三氨基酸插入。这些数据将二聚体人IgA上的pIgR结合位点定位到Cα3结构域的这个环结构上，该结构指导聚合抗体的黏膜分泌。我们提出，利用pIgR结合基序将抗原特异性dIgA和小分子药物递送至黏膜上皮用于治疗或许是可行的。
